Elsevier

Neuroscience

Volume 124, Issue 3, 2004, Pages 685-693
Neuroscience

Antinociception and modulation of rostral ventromedial medulla neuronal activity by local microinfusion of a cannabinoid receptor agonist

https://doi.org/10.1016/j.neuroscience.2003.10.001Get rights and content

Abstract

Systemic administration of a cannabinoid agonist produces antinociception through the activation of pain modulating neurons in the rostral ventromedial medulla (RVM). The aim of the present study was to determine how a cannabinoid receptor agonist acting directly within the RVM affects neuronal activity to produce behaviorally measurable antinociception. In lightly anesthetized rats, two types of RVM neurons have been defined based on changes in tail flick-related activity. On-cells increase firing (on-cell burst), whereas off-cells cease firing (off-cell pause), just prior to a tail flick. The cannabinoid receptor agonist WIN55,212–2 was microinfused directly into the RVM while monitoring tail flick latencies and on- and off-cell activity. Microinfusion of WIN55,212–2 (2.0 μg/μl and 0.4 μg/μl) reduced the tail flick-related on-cell burst, decreased the duration of the off-cell pause, and increased off-cell ongoing activity. These changes were prevented by co-infusing the CB1 receptor antagonist, SR141716A (0.35 μg/μl), with WIN55,212–2 (0.4 μg/μl). Furthermore, 2.0 μg/μl WIN55,212–2 delayed the onset of the off-cell pause and increased tail flick latencies. Microinfusion of WIN55,212–2 to brain regions caudal or lateral to the RVM had no effect on RVM neuronal activity or tail flick latencies. These results indicate that cannabinoids act directly within the RVM to affect off-cell activity, providing one mechanism by which cannabinoids produce antinociception.

Section snippets

Experimental animals and surgical preparation

All experiments were performed after the review and approval of the Institutional Animal Care and Use Committee at the University of California, San Francisco and carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All possible efforts were made to minimize the number of animals used and their suffering. Experiments were conducted using 67 male Sprague–Dawley rats (325–450 g; Bantin and Kingman, Hayward, CA, USA) injected with

Results

The effect of microinfusing vehicle, WIN 55,212–2 and WIN 55,212–2+SR141716A on tail flick latencies and neuronal activity was determined using a total of 67 animals. Neuronal activity and tail flick latencies were recorded for at least 20 min following the completion of each microinfusion. In some experiments, to determine the time-course of the drug effect, data were recorded for 45 min after the microinfusion. Recording sites were located within the RVM, including the nucleus raphe magnus,

Discussion

Previous experiments from this laboratory demonstrated changes in RVM neuronal activity and tail flick latencies following i.v. administration of the cannabinoid receptor agonist, WIN 55,212–2 (Meng et al., 1998). The current study evaluated whether these effects on neuronal activity and tail flick latencies could be mediated by cannabinoid receptors located locally within the RVM. Results from the current study demonstrate that microinfusion of a cannabinoid receptor agonist into the RVM

Acknowledgements

Supported by the U.S. National Institutes of Health (DA 14548 to I.D.M.). We thank Ichiro Harasawa for his critical reading and helpful suggestions.

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